Solving a medical mystery

Winter 2004/05

For the vast majority of people, a sore throat is no more than an
irritation that lasts a few days. But in a minority of cases — and
more frequently in children — a throat infection caused by
streptococcus bacteria can lead to devastating brain damage…

Paediatric neurologist Dr Russell Dale was working at Great Ormond
Street Hospital when he was struck by the terrifying and dramatic
nature of the symptoms he was seeing in some of his patients.
Previously healthy children would suddenly develop movement and
psychiatric disorders, to the extent that their parents described
them as having `changed personality overnight'.

Often these children required hospitalisation. Dr Dale started to
research the area in his spare time, but what began almost as a
hobby became more and more important to him, eventually leading to
an application for an Action Medical Research grant. "Having seen
the terrible effects on children, and their parents, I wanted to
understand what causes these brain disorders and do my best to
help," says Dr Dale.

Three years on, Dr Dale's research at the Neuroimmunology Unit in
London's Institute of Neurology has formed part of a great leap
forward in the medical world's understanding of this phenomenon. His
work may lead to treatments for a wide range of physical and
psychiatric disorders, from tics and obsessive behaviour to
Tourette's syndrome, Parkinson's disease and encephalitis lethargica
or `sleepy sickness'. And it is all due to a grant of £141,000 from
Action Medical Research.

What's the connection?
It seems incredible that something as banal as a sore throat might
cause brain damage. Dr Dale explained to Touching Lives how this can
happen: "When you get an infection of any sort, the body produces
antibodies to try to fight it off. The antibody usually recognises
which cell to attack by the kind of protein found on the cell's
surface.

"What we found in the laboratory stage of our research is that the
proteins on the surface of streptococcus bacteria are very similar
to those on the surface of brain cells. This means that antibodies
produced when you get a streptococcal throat infection can `cross-
react' — the antibodies produced to fight the sore throat attack the
brain as well. It's basically the body making a mistake and
overreacting. It thinks the brain cells are foreign, whereas in fact
they're not."

A wide range of symptoms
The particular range of symptoms is the result of damage to a part
of the mid brain called the basal ganglia, which seems particularly
vulnerable to the antibodies produced. "This part of the brain co-
ordinates and sends out information," says Dr Dale. "It acts as a
modulator, regulating the quality of movements and emotions."

So when this balancing system is damaged, both movements and
emotions are unregulated and can become extreme or unpredictable.
That's why the physical symptoms of the disease include the body
either making extra movements or moving too quickly, resulting in
tics or similar repeated movements, or moving too slowly, resulting
in the stiffness associated with, for example, Parkinson's disease.

Alongside these physical changes are arguably more important
psychiatric symptoms. Sufferers experience emotional changes,
including extreme anxiety, obsessive behaviour and depression. And
what makes these changes even more traumatic is the speed with which
they come on. "There's usually a lag of about two weeks between the
infection and the onset of the symptoms. But when they arise, the
onset is explosive — previously healthy children can suddenly become
very ill. Some even have to be hospitalised. It's extremely
distressing both for children and parents. And that's in part what
motivated me to do this research."

Developing a test, minimising suffering
What's so important about this new discovery is that bacterial
infections, and the antibodies they produce, are relatively easy to
treat. "The general aim of treatment is to remove the antibodies,
which can be done in two ways," says Dr Dale. "Steroids can be used
to suppress the immune system generally, so that fewer antibodies
are produced. But these are quite toxic drugs, with unpleasant side-
effects.

"Alternatively, more specific treatments can be used to remove just
the antibodies — that's a `cleaner' treatment with fewer side-
effects. There is now a test which looks for these antibodies so
that we can treat them directly, but it's very complicated and
expensive to administer, so we're looking for one we could use on
lots of patients. Ultimately an antibiotic could be developed to
reduce the brain damage and improve the patients' condition."

Not everyone who suffers from these disorders will end up with
permanent damage. The earlier they are treated, the less likely it
is that permanent damage will occur — which is why a test of the
kind Dr Dale is looking for is so important. And children are in
fact more receptive to treatment than adults. This is because, up to
the age of about 11, children's brains are more `plastic' than
adults' brains, which means that the brain is more able to take on
different roles and so respond quickly to treatment.

An historic discovery
Dr Dale's work forms part of a distinguished strand in the history
of medical research. "The idea of infection leading to a brain
disorder is very old," explains Dr Dale. "It's been known for over a
hundred years that one particular brain disorder, called Sydenham's
Chorea, is linked to streptococcus. What wasn't known before was how
many other types of brain disorder might be triggered by this sort
of infection."

After clinical work with 60 children with a variety of brain
disorders, together with his laboratory-based research, Dr Dale has
established a connection between the antibodies produced after
streptococcal infection and brain cell death in a much wider range
of conditions than was previously recognised. "This wider
recognition is very important for accurate diagnosis," says Dr
Dale. "Now, a child with any type of movement or psychiatric
disorder after a streptococcal throat infection will be examined for
these antibodies. And given how widespread some of these disorders
are, this could be relevant for up to one per cent of the
population."

What next?
This is only the beginning of the story for Dr Dale. There are still
a number of questions to be asked — why, for example, is it only the
streptococcal infection which causes sore throats that trigger this
brain damage, and not the other common streptococcal infections? "We
still don't understand the brain very well," says Dr Dale, "which is
one of the reasons I chose to specialise in neurology — it's a
fascinating area, with lots of scope for work in the future. And I
wanted to work in paediatrics in particular because working with
children and their parents is so much fun! I've had very positive
experiences as a paediatrician, and you feel you're doing good."

The importance of the Action Medical Research grant to Dr Dale's
work can't be overestimated. "I'm overwhelmingly grateful to the
Charity for supporting this project. Having seen the effects of this
disorder on sufferers, I know how important it is to try to find a
treatment. We simply wouldn't have been able to do this without
Action Medical Research."

Medical Mysteries
Dr Dale's work was featured on the BBC documentary `Medical
Mysteries' earlier this year. The documentary explored a particular
condition called encephalitis lethargica, or `sleepy sickness',
which causes a range of extreme symptoms, including paralysis,
uncontrollable movements, and speech disorders.

Sleepy sickness was brought to popular attention by the Hollywood
film `Awakenings' starring Robert de Niro. It had been thought that
the disease died out after the last major outbreak in the 1920s. But
the BBC programme picked up on a number of cases which have suddenly
appeared over the last few years, and explored the work being done
to try to explain the condition.

The programme featured Dr Dale explaining his alarm at coming across
patients with encephalitis lethargica — a disease he thought he
would never see. And when he let the medical community know that he
was interested in studying the disease, many more cases came to
light. It had long been thought that, as with Sydenham's Chorea,
there was a link between encephalitis lethargica and some kind of
infection — influenza was at one point the prime suspect.

But when he looked for a common factor, Dr Dale found that half the
patients with encephalitis lethargica had reported a sore throat
before they developed the disease. It was this that triggered Dr
Dale to consider streptococcus, the commonest cause of sore throats,
as a possible cause. And sure enough, blood tests showed that every
patient had been infected by a particular strain of streptococcus —
an invaluable insight into the cause of this devastating disease.

The eminent neurologist Dr Oliver Sachs (author of `The Man Who
Mistook His Wife for a Hat') was featured talking about his life-
long work with sufferers of encephalitis lethargica, and hailed Dr
Dale's work as "brilliant, and original, and maybe revolutionary."

Thanks go to the Barnwood House Trust for their support of this
grant.

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